Evidence from epidemiologic and animal model studies of autism (ASD) supports a role for pre- and postnatal immune and infectious factors in autism pathogenesis. However, associations with specific pathogens, patterns of immune response, fever and exposure to antibiotics, antipyretics, analgesics and micronutrients have not been rigorously addressed. This project will leverage the unique resources of the Norwegian Autism Birth Cohort (ABC) and the Center for Infection and Immunity (CII) for insights into the role of infection, immunity and inflammation in autism through pursuit of three complementary aims that address not only immune activation, fever and drug and micronutrient exposures during gestation per se, but also the timing of these phenomena. In Aim 1 we will investigate the relationship of infectious, immune and inflammatory events to ASD risk using prospective questionnaire data about the following exposures in ASD and control mother- child pairs: a) infection; b) presence, timing and duration of fever, c) autoimmune and allergic conditions, d) antipyretics (acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]), analgesics and antibiotics, and e) micronutrients that modify immune function (vitamin D, zinc) or mitigate antibiotic anti-folate effects (folate). In Aim 2 we will define the immune signatures associated with ASD using multiplexed immunoassays (Luminex) to compare levels of 61 immune/inflammatory molecules in plasma samples from ASD and control mothers (mid-gestation, birth) and children (umbilical cord blood). In Aim 3 we will examine the role of specifi infectious agents in ASD by measuring maternal and child antibodies to influenza virus; ToRCH pathogens T. gondii, rubellavirus, cytomegalovirus and herpes simplex viruses 1 and 2; and Group B streptococcus and E. coli using luciferase immunoprecipitation systems (LIPS) and multiplexed immunoassays (Luminex). In concert these aims have the potential to identify factors and biomarkers for ASD risk that could facilitate early diagnosis and intervention. The Research Council of Norway has reviewed the proposal and guaranteed funding to a maximum of NOK 5 million ($834,000), to support the Norwegian segment of the project, contingent on NIH support.